It is well known in the art that compounds of the formula: ##STR4## wherein R.sub.1 and R.sub.2 each individually are hydrogen, halogen, or nitro, or pharmaceutically acceptable salts thereof are antihypertensive agents. The most widely used representative of these compounds is 2-(2',6'-dichlorophenylamino)-imidazoline-(2), known as clonidine or chlophazoline.
Processes for the preparation of 2-(phenylamino)-imidazolines-(2) are described in a number of patents. Most frequently the processes involve reaction of N-phenyl-S-alkylisothiuronium salts with ethylenediamine and is cited in Belgian Pat. No. 623305, Dutch Patent Application Nos. 6,411,516, 6,613,830, U.S. Pat. No. 3,202,660, British Patent No. 1,034,938 and West German Pat. No. 1,303,141. Basic N-phenyl-S-alkylisothioureas and ethylenediamine mono-p-toluenesulphonate according to East German Pat. No. 68,511 may be used also.
2-(phenylamino)-imidazolines-(2) may be prepared also from: phenylthioureas and ethylenediamine according to Dutch Patent Application No. 6,411,516, British Pat. No. 1,034,938, and West German Pat. No. 2,163,306; N-phenyl-N'-nitroguanidines with ethylenediamine according to Bulgarian Pat. Nos. 12,390 and 12,393; phenylguanidines with ethylenediamine in a basic form or as mono-p-toluenesulphonate according to East German Pat. No. 68,510, French Pat. No. 1,577,129, British Pat. No. 1,230,583; phenylisocyanide dihalogenides with ethylenediamine according to East German Pat. No. 71,554, French Pat. Nos. 1,566,036 and 1,577,128, British Pat. No. 1,229,993, South African Pat. No. 6,706,503; from phenylcyanamides with monosalts of ethylenediamine according to East German Pat. No. 68,509 and British Pat. No. 1,230,482. Different 2-(phenylamino)-imidazolines-(2) are obtained by means of introducing substituents in the aromatic nucleus according to French Pat. Nos. 1,566,035 and 1,566,036; by means of reacting anilines with bis-(2-oxo-1-imidazolinyl)-phosphinechloride according to Bulgarian Pat. Nos. 12,391 and 12,394, or with 1-acylimindazoline-2 -one according to Bulgarian Patent Application No. 26,251. There are other variants of the above-mentioned known methods.
A disadvantage of the known methods is the unsatisfactory yield. In other cases a disadvantage appears to be the unstable intermediates which are difficult to purify, for example the cyanamides. Other weak points of the known methods are also the difficulties accompanying the isolation and the purification of 2-(phenylamino)-imidazolines-(2).
As stated hereinabove the invention also relates to new intermediate compounds used in the production of the 2-(phenylamino)-imidazolines. These intermediate compounds are N-phenyl-N'-acyl-S-alkylisothioureas.
There are familiar N-phenyl-N'-acylthioureas, for example from the publications of J. Douglas, F. Dains, J. Am. Chem. Soc. 56, 1408 (1934); R. Frank, P. Smith, Org. Synth. Coll. Vol. 3, New York, p. 736(1955), publications of At. Georgiev, K. Mondeshka and K. Andreev, Collection of Works from NIHFI, vol. 7, Sofia, p. 149 (1972) and also publication of B. Loevetal, J. Med. Chem., 15, p. 1026(1972). However, the N-phenyl-N'-acyl-s-alkylisothioureas have yet to be made until the present time.